Antimicrobial Activity of Aztreonam in Combination with Old and New β-Lactamase Inhibitors against MBL and ESBL Co-Producing Gram-Negative Clinical Isolates: Possible Options for the Treatment of Complicated Infections

Abstract

Metallo-β-lactamases (MBLs) are among the most challenging bacterial enzymes to overcome. Aztreonam (ATM) is the only β-lactam not hydrolyzed by MBLs but is often inactivated by co-produced extended-spectrum β-lactamases (ESBL). We assessed the activity of the combination of ATM with old and new β-lactamases inhibitors (BLIs) against MBL and ESBL co-producing Gram-negative clinical isolates. Six Enterobacterales and three non-fermenting bacilli co-producing MBL and ESBL determinants were selected as difficult-to-treat pathogens. ESBLs and MBLs genes were characterized by PCR and sequencing. The activity of ATM in combination with seven different BLIs (clavulanate, sulbactam, tazobactam, vaborbactam, avibactam, relebactam, zidebactam) was assessed by microdilution assay and time–kill curve. ATM plus avibactam was the most effective combination, able to restore ATM susceptibility in four out of nine tested isolates, reaching in some cases a 128-fold reduction of the MIC of ATM. In addition, relebactam and zidebactam showed to be effective, but with lesser reduction of the MIC of ATM. E. meningoseptica and C. indologenes were not inhibited by any ATM–BLI combination. ATM–BLI combinations demonstrated to be promising against MBL and ESBL co-producers, hence providing multiple options for treatment of related infections. However, no effective combination was found for some non-fermentative bacilli, suggesting the presence of additional resistance mechanisms that complicate the choice of an active therapy.

Diminished Susceptibility to Cefoperazone/Sulbactam and Piperacillin/Tazobactam in Enterobacteriaceae Due to Narrow-Spectrum β-Lactamases as Well as Omp Mutation

“…In addition, simultaneous analysis of the MICs of FEP, FPT, and FPZ delineated tazobactam as a distinctly less active inhibitor than zidebactam against strains producing TEM-1, SHV-1, and OXY-1 β-lactamases. It may be attributed to the dual activity of zidebactam, which can protect cefepime from hydrolysis by β-lactamases, but also bind the Gram-negative PBP2 and retain an excellent antibacterial activity ( Thomson et al 2019 ; Morroni et al 2021 ).…”

Predicting the Effects of Carbapenem/Carbapenemase Inhibitor Combinations against KPC-Producing Klebsiella pneumoniae in Time-Kill Experiments: Alternative versus Traditional Approaches to MIC Determination

“…However, the precise concentration ratios of antibiotics and inhibitors to use in time-kill experiments are not clearly understood. Most study designs use antimicrobial concentration as a multiple of the MIC, but the inhibitor is at constant concentration, similar to traditional MIC testing [ 18 , 19 , 20 ]. This approach does not consider antibiotic pharmacokinetics and therefore the actual antibiotic/inhibitor concentration ratios achieved in humans.…”

Antibiofilm Activity of β-Lactam/β-Lactamase Inhibitor Combination against Multidrug-Resistant Salmonella Typhimurium

“…This has led to the emergence of β-lactam resistance, which has become a serious threat to public health worldwide [9]. Recently, the use of β-lactamase inhibitors (BLIs), including clavulanic acid (CA), sulbactam (SUL), tazobactam (TB), avibactam (AB), and vaborbactam (VB), has gained attention as an alternative method with which to enhance the antimicrobial activity of β-lactams [10]. The commercial combination drugs of β-lactams and BLIs has been used for treating infectious diseases, for instance, ampicillin + SUL, piperacillin + TB, ceftolozane + TB, ceftazidime + AB, and meropenem + VB against MDR bacteria [11,12].…”